PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation.
IKKbeta serves as a central intermediate signaling molecule in the activation of the NF-kappaB pathway. However, the precise mechanism for the termination of IKKbeta activity is still not fully understood. Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, PPM1A and PPM1B, as IKKbeta phosphatases. Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation. PPM1A and PPM1B associate with the phosphorylated form of IKKbeta, and the interaction between PPM1A/PPM1B and IKKbeta is induced by TNFalpha in a transient fashion in the cells. Furthermore, knockdown of PPM1A and PPM1B expression enhances TNFalpha-induced IKKbeta phosphorylation, NF-kappaB nuclear translocation and NF-kappaB-dependent gene expression. These data suggest that PPM1A and PPM1B play an important role in the termination of TNFalpha-mediated NF-kappaB activation through dephosphorylating and inactivating IKKbeta.
Sun
Wenjing
W
Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, United States.
Yu
Yang
Y
Dotti
Gianpietro
G
Shen
Tao
T
Tan
Xiaojie
X
Savoldo
Barbara
B
Pass
Amy K
AK
Chu
Meijin
M
Zhang
Dekai
D
Lu
Xiongbin
X
Fu
Songbin
S
Lin
Xia
X
Yang
Jianhua
J
D001483:Base Sequence; D002460:Cell Line; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D047468:Immunoprecipitation; D015850:Interleukin-6 / Q000378:metabolism; D008163:Luminescent Measurements; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D000071636:Protein Phosphatase 2C; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase; C000607456:PPM1A protein, human; C000607457:PPM1B protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C